Search results for: symbiosis receptor kinase (SYMRK)

Authors: Deepika Saini, Sandeep Jain, Ajay Kumar

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The quinoline scaffold is one of the most widely studied in the discovery of derivatives with various heterocyclic moieties due to its potential antimalarial activities. In the present study, a chalcone series of quinoline derivatives clubbed with pyrazole were synthesized to evaluate their antimalarial property by in vitro schizont maturation inhibition assay against both chloroquine sensitive, 3D7 and chloroquine resistant, RKL9 strain of Plasmodium falciparum. Further, top five compounds were studied for in vivo preclinical study for antimalarial potential against P. berghei in Swiss albino mice. To understand the mechanism of synthesized analogues, they were screened computationally by molecular docking techniques. Compounds were docked into the active site of a protein receptor, Plasmodium falciparum Cysteine Protease Falcipain-2. The compounds were successfully synthesized, and structural confirmation was performed by FTIR, 1H-NMR, mass spectrometry and elemental analysis. In vitro study suggested that the compounds 5b, 5g, 5l, 5s and 5u possessed best antimalarial activity and further tested for in vivo screening. Compound 5u (CH₃ on both rings) with EC₅₀ 0.313 & 0.801 µg/ml against CQ-S & CQ-R strains of P. falciparum respectively and 78.01% suppression of parasitemia. The molecular docking studies of the compounds helped in understanding the mechanism of action against falcipain-2. The present study reveals the binding signatures of the synthesized ligands within the active site of the protein, and it explains the results from in vitro study in their EC₅₀ values and percentage parasitemia.

Keywords: antimalarial activity, chalcone, docking, quinoline

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Authors: Jiandong Ren, Lijun Zhao, Peng Chen

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Nafamostat (NA), a synthetic broad-spectrum serine protease inhibitor, has been routinely employed for the treatment of acute pancreatitis (AP) and other inflammatory-associated diseases in some East Asia countries. Although the potent inhibitory activity against inflammation-related proteases such as thrombin, trypsin, kallikrein, plasmin, coagulation factors and complement factors is generally considered to be responsible for the anti-inflammatory effects of NA, precise target and molecular mechanism underlying the anti-inflammatory activity in the treatment of AP remain largely unknown yet. As an intracellular inflammatory signaling platform, the NOD-like receptor protein 3 (NLRP3) inflammasome is recently identified to be involved in the development of AP. In present study, we have revealed that NA alleviated pancreatic injury in a caerulein-induced AP model by inhibiting the NLRP3 inflammasome activation in pancreas. Mechanistically, NA interacted with HDAC6, a cytoplasmic deacetylase implicated in the NLRP3 inflammasome pathway, and efficiently abrogated the function of HDAC6. This property enabled NA to influence HDAC6 dependent NF-κB transcriptional activity and thus block NF-κB-driven transcriptional priming of NLRP3 inflammasome. Moreover, NA exerted the potential to interfere HDAC6-mediated intracellular transport of NLRP3, thereby leading to the failure of NLRP3 inflammasome activation. Our current work has provided valuable insight into the molecular mechanism underlying the immunomodulatory effect of NA in treatment of AP, highlighting its promising application in prevention of NLRP3 inflammasome-associated inflammatory pathological damage.

Keywords: acute pancreatitis, HDAC6, nafamostat, NLRP3 inflammasome

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Authors: Lee Seungheon, Kim Ba-Ro

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In this study, the anti-stress effects of the ethanolic extract of Hydrangeae Dulcis Folium (EHDF) were investigated. To determine the effects of EHDF on physical stress, changes in the whole-body cortisol level and behaviour were monitored in zebrafish. To induce physical stress, we used the net handling stress (NHS). Fish were treated with EHDF for 6 min before they were exposed to stress, and the fish were either evaluated via behavioural tests, including a novel tank test and an open field test or sacrificed to collect body fluid from the whole body. The results indicate that increased anxiety-like behaviours in the novel tank test and open field test under stress were recovered by treatment with EHDF at 5, 10 and 20 mg/L (P < 0.05). Moreover, compared with the normal group, which was not treated with NHS, the whole-body cortisol level was significantly increased by treatment with NHS in the control group. Compared with the control group, pre-treatment with EHDF at concentrations of 5, 10 and 20 mg/L for 6 min significantly prevented the increase in the whole-body cortisol level induced by NHS (P < 0.05). In addition, adrenocorticotropin hormone (ACTH) challenge studies showed that EHDF completely blocked the effects of ACTH (0.2 IU/g, IP) on cortisol secretion. These results suggest that EHDF may be a good anti-stress candidate and that its mechanism of action may be related to its positive effects on cortisol release.

Keywords: net handling stress, zebrafish, hydrangeae dulcis folium, whole-body cortisol, novel tank test, open field test

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Authors: Nuri Başpınar, Abdullah Başoğlu, Özgür Özdemir, Çağlayan Özel, FundaTerzi, Özgür Yaman

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Current research is targeting new molecular mechanisms that underlie non-alcoholic fatty liver disease (NAFLD) and associated metabolic disorders like nonalcoholic steatohepatitis (NASH). Forty New Zealand White rabbits have been used and fed a high protein (HP) and energy diet based on grains and containing 11.76 MJ/kg. Boron added to 3 experimental groups’ drinking waters (30 mg boron/L) as boron compounds. Biochemical analysis including boron levels, and nuclear magnetic resonance (NMR) based metabolomics evaluation, and mRNA expression of peroxisome proliferator-activated receptor (PPAR) family were performed. LDL-cholesterol concentrations alone were decreased in all the experimental groups. Boron levels in serum and feces were increased. Content of acetate was in about 2x higher for anhydrous borax group, at least 3x higher for boric acid group. PPARα mRNA expression was significantly decreased in boric acid group. Anhydrous borax attenuated mRNA levels of PPARα, which was further suppressed by boric acid. Boron supplementation decreased the degenerative alterations in hepatocytes. Except borax group other boron groups did not have a pronounced change in tubular epithels of kidney. In conclusion, high protein and energy diet leads hepatocytes’ degenerative changes which can be prevented by boron supplementation. Boric acid seems to precede in this effectiveness.

Keywords: high protein and energy diet, boron, metabolomics, transcriptomic

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Authors: Mahabub Alam, Mohammad Mahmudul Hassan, M. Hasanuzzaman, M. Ahasanul Hoque

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Animals are transported from one place to another for different purposes in Bangladesh. However, the potential effect of long-distance transport on cattle health has not frequently been studied. Therefore, this study was conducted to assess health conditions of cattle transported from a long distance to Chittagong in Bangladesh. A total of 100 adult cattle, regardless of breed and sex, were selected at Benapole live cattle market in Jessore between August and September 2015 for the study. Blood samples were taken from 50 randomly selected cattle at 0 hours before transportation, just after transportation, at 12-16 hours post-conclusion of transportation, and 24 hours after transportation. The external health conditions and injuries of the cattle were assessed by close inspection, and the trader was interviewed using the structured questionnaire. Images of cattle injuries were taken with a camera. The basic internal health of the cattle was evaluated using standard hemato-biochemical tests. Animals were fasted and remained standing within a small space allocation (8-10 sq feet/animal) in the vehicle during transportation. Animals were provided only with paddy straw and water prior to selling at the destination market. The overall frequency of cattle injuries varied significantly (26% before vs. 47% after transportation; p < 0.001). The frequency of different cattle injuries also significantly varied by types such as abrasion (11% vs. 21%; p < 0.05) and barbed wire injury (9% vs. 18%; p < 0.05). Single cattle injury differed significantly (21% vs. 36%; p < 0.001). Cattle health conditions varied significantly (nasal discharge: 15% vs. 28%; p < 0.05; diarrhea: 15% vs. 23%; p < 0.05 and severe dehydration: 8% vs. 20%; p < 0.001). The values of hemoglobin (Hb), total erythrocyte count (TEC), total leukocyte count (TLC), lymphocyte (L), neutrophil (N) and eosinophil (E) varied significantly (p ≤ 0.01) (Hb: 11.1mg/dl vs. 12.3mg/dl; TEC: 4.7 million/ml vs. 5.7million/ml; TLC: 6.2 thousand/ml vs. 7.3 thousand/ml; L: 61.7% vs. 58.1%; N: 29.7% vs. 32.8%; E: 3.8% vs. 4.7%). The values of serum total protein (TP), creatine kinase (CK), triglyceride (TG), calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) significantly differed (p ≤ 0.05) (TP: 6.8g/dl vs. 8.2g/dl; CK:574.9u/l vs. 1288u/l; TG: 104.7mg/dl vs. 127.7mg/dl; Ca: 11.3mg/dl vs. 13mg/dl; P: 7.3mg/dl vs. 7.6mg/dl; ALP: 303u/l vs. 363u/l). The identified status of external and internal health conditions of the cattle for trading purpose due to long-distance transportation in the present study indicates a high degree of transport stress and poor animal welfare.

Keywords: animal welfare, cattle, external and internal health conditions, transportation

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Authors: Irma Gabriela Lopez-Moreno, Elva Perez-Luque, Herlinda Aguilar-Zavala

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Introduction: Type 2 Diabetes Mellitus (T2DM) is characterized by combination of insulin resistance and deterioration of insulin secretion. Sfrp5 is a protein that antagonizes Wnt5a proteins by preventing it from reaching its receptor and activating the Wnt/β-catenin signaling pathway, this pathway is one of the most important regulators of adipogenesis. Although metformin decreases glucose levels its mechanisms of action are not fully known but it has been implicated in the inhibition of the Wnt/β-catenin signaling pathway. Objective: The objective was evaluating the effects of metformin on serum levels of Sfrp5 in patients with T2DM treated and not treated with metformin. Methods: Two groups of patients were selected: one group of T2DM patients treated with metformin (n = 35) and another group of subjects with recent diagnosis of T2DM untreated (n = 35) with a mean age of 48 ± 9 years. In these subjects anthropometric measures were taken as weight, height, waist and hip circumference, were calculated the percentage of body fat, visceral fat and muscle mass. In addition, were measured glucose levels, lipid profile, adiponectin and Sfrp5. Results: Sfrp5 were higher in metformin-treated patients compared to the untreated group (19.9 vs 13.6 ng/mL p < 0.001), a negative correlation was found between Sfrp5 levels and total cholesterol levels (r= -0.25, p = 0.03) and percentage of visceral fat (r = -0.26, p = 0.03) and a positive correlation with HDL cholesterol levels (r = 0.31, p = 0.01) and adiponectin (r=0.65, p = < 0.001). Conclusions: The findings show that metformin consumption increased levels of Sfrp5, which may lead to a decrease in the activation of the WNT/β-catenin pathway impacting on adipogenesis.

Keywords: adiponectin, diabetes, metformin, Sfrp5

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Authors: Changde Zhang, Qiang Zhang, Shilong Zheng, Jiawang Liu, Shanchun Guo, Qiu Zhong, Guangdi Wang

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Fulvestrant was approved by FDA to treat breast cancer as a selective estrogen receptor downregulator (SERD) with intramuscular injection administration. ZB716, a fulvestarnt-3 boronic acid, is an SERD with comparable anticancer effect to fulvestrant, but could produce good pharmacokinetic properties under oral administration with mice or rat models. To understand why ZB716 produced much better oral bioavailability, it was proposed that the boronic acid blocked the phase II direct biotransformation with the hydroxyl group on the 3 position of the aromatic ring on fulvestrant. In this study, ZB716 or fulvestrant was incubated with human liver microsome and oxidation cofactor NADPH in vitro. Their metabolites after oxidation were profiled with the Q-Exactive, a high-resolution mass spectrometer. The result showed that ZB716 blocked the forming of hydroxyl groups on its benzene ring except for the oxidation of C-B bond forming fulvestrant in its metabolites, and the concentration of fulvestrant with one more hydroxyl group found in the metabolites from incubation with fulvestrant was about 34 fold high as that formed from incubation with ZB716. Compared to fulvestrant, ZB716 is expected to be much difficult to be further bio-transformed into more hydrophilic compounds, to be difficult excreted out of blood system, and to have longer residence time in blood, which can lead to higher oral bioavailability. This study provided evidence to explain the high bioavailability of ZB716 after oral administration from the perspective of its difficulty of oxidation, a phase I biotransformation, on positions on its aromatic ring.

Keywords: biotransformation, fulvestrant, metabolite profiling, ZB716

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Authors: Youjeong Hwang

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Purpose: Insulin-like growth factor-I (IGF-I) promotes B-cell development, immunoglobulin formation, and interleukin-6 (IL-6) production, then regulate the immune response and inflammation. As IGF-I and their receptor also exist in the periodontal tissue, they may affect the immune response caused by periodontal pathogens in aggressive periodontitis (AgP) patients. The function of IGF is regulated by IGF binding proteins (IGFBPs), and IGFBP-3 is known to most abundant in plasma. The aim of the present study was to assess the concentration of IGF-I and IGFBP-3 in plasma and gingival crevicular fluid (GCF) in AgP patients and to find out their association. Methods: Nine patients with AgP (test group) and nine healthy subjects (control group) were included in this study. None of the subjects had a history of systemic disease, smoking or steroids medication. GCF samples were collected by microcapillary pipettes and plasma samples were obtained by venipuncture. Probing pocket depth (PD), clinical attachment level (CAL) and bleeding on probing (BOP) were recorded. Samples were assayed for IGF-I and IGFBP-3 levels using ELISA. Results: Mean IGF-I level in GCF was higher in the test group than control. Mean IGF-I level in plasma and IGFBP-3 level in GCF and plasma in control group were higher than that of the test group. However, there was no statistical significance (p > 0.05). The mean level of IGF-I and IGFBP-3 in GCF was lower than those in plasma. Mean IGF-I level in plasma showed a negative correlation with PD and CAL (p < 0.05) in both groups. The levels of IGF-I and IGFBP-3 in GCF seemed to be negatively correlated with BOP in the test group (p < 0.05). Conclusions: The difference in the level of IGF-I and IGFBP-3 between AgP and healthy subjects was not significant. Further studies that explain the mechanism of the protective role of IGF-I with more samples are needed.

Keywords: aggressive periodontitis, pathogenesis, insulin-like growth factor, insulin-like growth factor binding protein

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Authors: Yasser A. Ahmed, Juleen M Dickson, Evan S. Krystofiak, Julie A. Oliver

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Cancer cells urgently need folate to support their rapid division. Folate receptors (FR) are over-expressed on a wide range of tumor cells, including breast cancer cells. FR are distributed over the entire surface of cancer cells, but are polarized to the apical surface of normal cells. Targeting of cancer cells using specific surface molecules such as folate receptors may be one of the strategies used to kill cancer cells without hurting the neighing normal cells. The aim of the current study was to try a method of SEM detecting FR in a murine breast cancer cell model (4T1 cells) using secondary antibody conjugated to gold or gold-coated magnetite nanoparticles. 4T1 cells were suspended in RPMI medium witth FR antibody and incubated with secondary antibody for fluorescence microscopy. The cells were cultured on 30mm Thermanox coverslips for 18 hours, labeled with FR antibody then incubated with secondary antibody conjugated to gold or gold-coated magnetite nanoparticles and processed to scanning electron microscopy (SEM) analysis. The fluorescence microscopy study showed strong punctate FR expression on 4T1 cell membrane. With SEM, the labeling with gold or gold-coated magnetite conjugates showed a similar pattern. Specific labeling occurred in nanoparticle clusters, which are clearly visualized in backscattered electron images. The 4T1 tumor cell model may be useful for the development of FR-targeted tumor therapy using gold-coated magnetite nano-particles.

Keywords: cancer cell, nanoparticles, cell culture, SEM

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Authors: Wajid Rehman, Sirajul Haq, Bakhtiar Muhammad, Syed Fahad Hassan, Amin Badshah, Muhammad Waseem, Fazal Rahim, Obaid-Ur-Rahman Abid, Farzana Latif Ansari, Umer Rashid

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Five novel triorganotin (IV) compounds have been synthesized and characterized. The tin atom is penta-coordinated to assume trigonal-bipyramidal geometry. Using in silico derived parameters; the objective of our study is to design and synthesize promiscuous antibacterials potent enough to combat resistance. Among various synthesized organotin (IV) complexes, compound 5 was found as potent antibacterial agent against various bacterial strains. Further lead optimization of drug-like properties was evaluated through in silico predictions. Data mining and computational analysis were utilized to derive compound promiscuity phenomenon to avoid drug attrition rate in designing antibacterials. Xanthine oxidase and human glucose- 6-phosphatase were found as only true positive off-target hits by ChEMBL database and others utilizing similarity ensemble approach. Propensity towards a-3 receptor, human macrophage migration factor and thiazolidinedione were found as false positive off targets with E-value 1/4> 10^-4 for compound 1, 3, and 4. Further, displaying positive drug-drug interaction of compound 1 as uricosuric was validated by all databases and docked protein targets with sequence similarity and compositional matrix alignment via BLAST software. Promiscuity of the compound 5 was further confirmed by in silico binding to different antibacterial targets.

Keywords: antibacterial activity, drug promiscuity, ADMET prediction, metallo-pharmaceutical, antimicrobial resistance

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Authors: Azza H. El-Medany, Hanan H. Hagar, Jamila H. El-Medany

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Ulcerative colitis (UC) is one of chronic inflammatory diseases primarily affecting colon with unknown etiology. Some researches papers mentioned the possibility of the use of drugs that affect the angiotensin II in reducing the complication of ulcerative colitis. The aim of the present study is to evaluate the potential protective and therapeutic effects of captopril and valsartan on ulcerative colitis induced experimentally in rats using acetic acid. The results were assessed by histological assessment of colonic tissues and measurement of malondialdehyde (MDA), tumor necrosis factor (TNF-α), transforming growth factor (TGF-1B), angiotensin converting enzyme (ACE), reduced glutathione (GSH) and platelet activating factor (PAF) levels in colonic tissues. Oral pre-treatment with captopril or valsartan in a dose of 30 mgkg-1 body weight for 2 weeks before induction of colitis (prophylactic groups) and continuously for 2 weeks after induction (therapeutic groups) significantly reduce MDA, TNF-α, PAF, TGF-1B and ACE levels in colonic tissues as compared to acetic acid control group. Also, a significant increase in GSH level was observed in colonic tissues. Captopril and valsartan attenuated the macroscopic and microscopic colonic damage induced by acetic acid. These results suggest that either captopril or valsartan may be effective as prophylactic or treatment of UC through inhibition of ACE and scavenging effect on oxygen-derived free radicals.

Keywords: captopril, valsartan, angiotensin converting enzyme, reduced glutathione, tumor necrosis factor

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Authors: R. Pravin Kumar, L. Roopa

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Enzymes are molecular machines used in various industries such as pharmaceuticals, cosmetics, food and animal feed, paper and leather processing, biofuel, and etc. Nevertheless, this has been possible only by the breath-taking efforts of the chemists and biologists to evolve/engineer these mysterious biomolecules to work the needful. Main agenda of this enzyme engineering project is to derive screening and selection tools to obtain focused libraries of enzyme variants with desired qualities. The methodologies for this research include the well-established directed evolution, rational redesign and relatively less established yet much faster and accurate insilico methods. This concept was initiated as a Receptor Rependent-4Dimensional Quantitative Structure Activity Relationship (RD-4D-QSAR) to predict kinetic properties of enzymes and extended here to study transaminase by a 7D QSAR approach. Induced-fit scenarios were explored using Quantum Mechanics/Molecular Mechanics (QM/MM) simulations which were then placed in a grid that stores interactions energies derived from QM parameters (QMgrid). In this study, the mutated enzymes were immersed completely inside the QMgrid and this was combined with solvation models to predict descriptors. After statistical screening of descriptors, QSAR models showed > 90% specificity and > 85% sensitivity towards the experimental activity. Mapping descriptors on the enzyme structure revealed hotspots important to enhance the enantioselectivity of the enzyme.

Keywords: QMgrid, QM/MM simulations, RD-4D-QSAR, transaminase

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Authors: Masocorro Gawned, Stephen Myers, Guat Siew Chew

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Nuclear Receptors (NR) are a super family of transcription factors that play a major role in lipid and glucose metabolism in skeletal muscle. Recently, pharmacological evidence supports the view that stimulation of nuclear receptors alleviates Type 2 Diabetes (T2D). The orphan nuclear receptors (ONR) are members of the nuclear receptor (NR) superfamily whose ligands and physiological functions remain unknown. To date, no systematic studies have been carried out to screen for ONRs expressed in insulin resistant (IR) skeletal muscle cells. Therefore, in this study, we have established a model for IR by treating C2C12 skeletal muscle cells with insulin (10nM) for 48 hours. Western Blot analysis of phosphorylated AKT confirmed IR. Real-time quantitative polymerase chain reaction (qPCR) results highlighted key ONRs including NUR77 (NR4A1), NURR1 (NR4A2) and NOR1 (NR4A3) which have been associated with fatty acid oxidation regulation and glucose homeostasis. Increased mRNA expression levels of estrogen-related receptors (ERRs), REV-ERBα, NUR77, NURR1, NOR1, in insulin resistant C2C12 skeletal muscle cells, indicated that these ONRs could potentially play a pivotal regulatory role of insulin secretion in lipid metabolism. Taken together, this study has successfully contributed to the complete analysis of ONR in IR, and has filled in an important void in the study and treatment of T2D.

Keywords: type 2 diabetes, orphan nuclear receptors, transcription receptors, quantitative mRNA expression

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Authors: Xiaoping Su, Gabriel G. Malouf

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Introduction: Breast cancer is a heterogeneous disease that can be classified in 4 subgroups using transcriptional profiling. The role of lncRNA expression in human breast cancer biology, prognosis, and molecular classification remains unknown. Methods and results: Using an integrative comprehensive analysis of lncRNA, mRNA and DNA methylation in 900 breast cancer patients from The Cancer Genome Atlas (TCGA) project, we unraveled the molecular portraits of 1,700 expressed lncRNA. Some of those lncRNAs (i.e, HOTAIR) are previously reported and others are novel (i.e, HOTAIRM1, MAPT-AS1). The lncRNA classification correlated well with the PAM50 classification for basal-like, Her-2 enriched and luminal B subgroups, in contrast to the luminal A subgroup which behaved differently. Importantly, estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Gene set enrichment analysis for cis- and trans-acting lncRNA showed enrichment for breast cancer signatures driven by breast cancer master regulators. Almost two third of those lncRNA were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that lncRNA expression may result in increased activity of neighboring genes. Differential analysis of gene expression profiling data showed that lncRNA HOTAIRM1 was significantly down-regulated in basal-like subtype, and DNA methylation profiling data showed that lncRNA HOTAIRM1 was highly methylated in basal-like subtype. Thus, our integrative analysis of gene expression and DNA methylation strongly suggested that lncRNA HOTAIRM1 should be a tumor suppressor in basal-like subtype. Conclusion and significance: Our study depicts the first lncRNA molecular portrait of breast cancer and shows that lncRNA HOTAIRM1 might be a novel tumor suppressor.

Keywords: lncRNA profiling, breast cancer, HOTAIRM1, tumor suppressor

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Authors: Sabri Sudirman, Yuan-Hua Hsu, Zwe-Ling Kong

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Male reproductive dysfunction is predominantly due to insulin resistance and hyperglycemia result in inflammation and oxidative stress. Furthermore, nanotechnology provides an alternative approach to improve the bioavailability of natural active food ingredients. Therefore, the aim of this study were to investigate nanoencapsulated triterpenoids from petri-dish cultured Antrodia cinnamomea (PAC) nanoparticles whether it could increase the bioavailability; in addition, the anti-inflammatory and anti-oxidative effects could more effectively ameliorate the reproductive function of diabetic male rats. First, PAC encapsulated in chitosan-silica nanoparticles (Nano-PAC) were prepared by biosilicification method. Scanning electron micrographs confirm the average particle size is about 30 nm, and the encapsulation efficiency is 83.7% by HPLC. Diabetic male Sprague-Dawley rats were induced by high fat diet (40% kcal from fat) and streptozotocin (35 mg/kg). Nano-PAC was administered by oral gavage in three doses (4, 8 and 20 mg/kg) for 6 weeks. Besides, metformin (300 mg/kg) and nanoparticles (Nano) were treated as the positive and negative control respectively. Results indicated that 4 mg/kg Nano-PAC administration for 6 weeks improved hyperglycemia, insulin resistance, and also reduced advanced glycation end products in plasma. In addition, 8 mg/kg Nano-PAC ameliorated morphological of testicular seminiferous tubules, sperm morphology and motility, reactive oxygen species production and mitochondrial membrane potential. Moreover, 20 mg/kg Nano-PAC restored reproductive endocrine system function and increased KiSS-1 level in plasma. In plasma or testis anti-oxidant superoxide dismutase, glutathione peroxidase and catalase were increased whereas malondialdehyde, as well as pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, and interferon-gamma, decreased. Most importantly, 8 mg/kg Nano-PAC down-regulated the oxidative stress induced c-Jun N-terminal kinase (JNK) signaling pathway. Our study successfully nanoencapsulated PAC to form nanoparticles and low-dose Nano-PAC improved diabetes-induced hyperglycemia, inflammation and oxidative stress to ameliorate the reproductive function of diabetic male rats.

Keywords: Antrodia cinnamomea, diabetes mellitus, male reproduction, nanoparticles

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Authors: Mathilde Kirkegaard

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The paper will focus on management of heritage that integrates the local community, and argue towards an obligation to integrate this social aspect in heritage management. By broadening the understanding of heritage, a sustainable heritage management takes its departure in more than a continual conservation of the physicality of heritage. The social aspect, or the local community, is in many govern heritage management situations being overlooked and it is not managed through community based urban planning methods, e.g.: citizen-inclusion, a transparent process, informative and inviting initiatives, etc. Historical sites are often being described by embracing terms such as “ours” and “us”: “our history” and “a history that is part of us”. Heritage is not something static, it is a link between the life that has been lived in the historical frames, and the life that is defining it today. This view on heritage is rooted in the strive to ensure that heritage sites, besides securing the national historical interest, have a value for those people who are affected by it: living in it or visiting it. Antigua Guatemala is a UNESCO-defined heritage site and this site is being ‘threatened’ by tourism, habitation and recreation. In other words: ‘the use’ of the site is considered a threat of the preservation of the heritage. Contradictory the same types of use (tourism and habitation) can also be considered development ability, and perhaps even a sustainable management solution. ‘The use’ of heritage is interlinked with the perspective that heritage sites ought to have a value for people today. In other words, the heritage sites should be comprised of a contemporary substance. Heritage is entwined in its context of physical structures and the social layer. A synergy between the use of heritage and the knowledge about the heritage can generate a sustainable preservation solution. The paper will exemplify this symbiosis with different examples of a heritage management that is centred around a local community inclusion. The inclusive method is not new in architectural planning and it refers to a top-down and bottom-up balance in decision making. It can be endeavoured through designs of an inclusive nature. Catalyst architecture is a planning method that strives to move the process of design solutions into the public space. Through process-orientated designs, or catalyst designs, the community can gain an insight into the process or be invited to participate in the process. A balance between bottom-up and top-down in the development process of a heritage site can, in relation to management measures, be understood to generate a socially sustainable solution. The ownership and engagement that can be created among the local community, along with the use that ultimately can gain an economic benefit, can delegate the maintenance and preservation. Informative, inclusive and transparent planning methods can generate a heritage management that is long-term due to the collective understanding and effort. This method handles sustainable management on two levels: the current preservation necessities and the long-term management, while ensuring a value for people today.

Keywords: community, intangible, inclusion, planning

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Authors: Benchouala Amira, Bojic Clement, Poupin Pascal, Cossu Leguille-carole

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The objective of this study is to evaluate in vitro the cytotoxic and androgenic potential of several antifungal molecules (amphotericin B, econazole, ketoconazole and miconazole) on MDA-Kb2 cell lines. This biological model is an effective tool for the detection of endocrine disruptors because it responds well to the main agonist of the androgen receptor (testosterone) and also to an antagonist: flutamide. The cytotoxicity of each chemical compound tested was measured using an MTT assay (tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) which measures the activity of the reductase function of mitochondrial succinate dehydrogenase enzymes of cultured cells. This complementary cytotoxicity test is essential to ensure that the effects of reduction in luminescence intensity observed during androgenic tests are only attributable to the anti-androgenic action of the compounds tested and not to their possible cytotoxic properties. Tests of the androgenic activity of antifungals show that these compounds do not have the capacity to induce transcription of the luciferase gene. These compounds do not exert an androgenic effect on MDA-Kb2 cells in culture for the environmental concentrations tested. The addition of flutamide for the same tested concentrations of antifungal molecules reduces the luminescence induced by amphotericin B, econazole and miconazole, which is explained by a strong interaction of these molecules with flutamide which may have a greater toxic effect than when tested alone. The cytotoxicity test shows that econazole and ketoconazole can cause cell death at certain concentrations tested. This cell mortality is perhaps induced by a direct or indirect action on deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or proteins necessary for cell division.

Keywords: cytotoxicity, androgenic potential, antifungals, MDA-Kb2

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Authors: Okhee Woo

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Purpose: The aim of this study is to evaluate 2-year cumulative effective radiation dose and cumulative organ dose on regular follow-up computed tomography (CT) scans in patients with breast cancer and to establish personalized low-dose CT protocol. Methods and Materials: A retrospective study was performed on the patients with breast cancer who were diagnosed and managed consistently on the basis of routine breast cancer follow-up protocol between 2012-01 and 2016-06. Based on ICRP (International Commission on Radiological Protection) 103, the cumulative effective radiation doses of each patient for 2-year follow-up were analyzed using the commercial radiation management software (Radimetrics, Bayer healthcare). The personalized effective doses on each organ were analyzed in detail by the software-providing Monte Carlo simulation. Results: A total of 3822 CT scans on 490 patients was evaluated (age: 52.32±10.69). The mean scan number for each patient was 7.8±4.54. Each patient was exposed 95.54±63.24 mSv of radiation for 2 years. The cumulative CT radiation dose was significantly higher in patients with lymph node metastasis (p = 0.00). The HER-2 positive patients were more exposed to radiation compared to estrogen or progesterone receptor positive patient (p = 0.00). There was no difference in the cumulative effective radiation dose with different age groups. Conclusion: To acknowledge how much radiation exposed to a patient is a starting point of management of radiation exposure for patients with long-term CT follow-up. The precise and personalized protocol, as well as iterative reconstruction, may reduce hazard from unnecessary radiation exposure.

Keywords: computed tomography, breast cancer, effective radiation dose, cumulative organ dose

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Authors: Rozeena Shaikh, Syed M Shahid, Jamil Ahmad, Qaisar Mansoor, Muhammad Ismail, Abid Azhar

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Introduction: Diabetes mellitus (DM) is a prevalent non-communicable disease worldwide. In most high-income countries as well as middle-income and low- income countries. DM is among the top causes of deaths. DM may lead to many vascular complications like hypertension, nephropathy, retinopathy, neuropathy, and foot. Diabetic nephropathy (DN) characterized by persistent albuminuria is a leading cause of end stage renal failure (ESRF). Pathogenesis of diabetic nephropathy is implicated by the polymorphisms in genes encoding the components of reninangiotensin- aldosteron system (RAAS) which include angiotensinogen (AGT), angiotensin-II receptor and particularly angiotensin converting enzyme (ACE) gene. Method: Study subjects include 110 control, 110 patients with DM without hypertension, 110 patients with DM with hypertension and 110 patients with DN. Blood samples were collected for Biochemical analysis and PCR and sequencing for the specific region of both genes. Results: The frequency of DD genotype and D allele of ACE (I/D) was significantly (p<0.05) high in DM normotensive, DM hypertensive and DN patients when compared to control. The ACE G2350A genotypes and allele frequencies were significantly different (p<0.05) in DM hypertensive patients as compared to control and DN, while no difference was observed between DM normotensive and DN when compared to control. The genotypes and alleles of AGT (M268T) polymorphism were significantly different (p<0.05) in DM normotensive, DM hypertensive and DN when compared to control. Conclusion: The DD genotype and D allele of ACE (I/D), GG genotype and G allele of ACE (G2350A) and the TT genotype and T allele of AGT (M268T) polymorphism have shown a significant difference in genotype and allele frequencies between controls and patients.

Keywords: genetic variations, ACE, AGT, diabetes mellitus, diabetic nephropathy, Pakistan

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Authors: Divya Vohora, Md. Jamir Anwar

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Antiepileptic drugs (AEDs)-induced adverse consequences on bone are now well recognized. Despite this, there is limited data on the effect of anti-osteoporotic therapies on AEDs-induced bone loss. Both phenytoin (PHT) and sodium valproate (SVP) inhibit human aromatase enzyme and stimulate microsomal catabolism of oestrogens. Estrogen deficiency states are known to reduce the deposition of transforming growth factor-β (TGF-β3), a bone matrix protein, having anti-osteoclastic property. Thus, an attempt was made to investigate the effect of raloxifene, a selective oestrogen receptor modulator, in comparison with CVD supplementation, on PHT and SVP-induced alterations in bone in mice. Further, the effect of raloxifene on seizures and on the antiepileptic efficacy of AEDs was also investigated. Swiss strains of female mice were treated with PHT (35 mg/kg, p.o.) and SVP (300 mg/kg, p.o.) for 120 days to induce bone loss as evidenced by reduced bone mineral density (BMD) and altered bone turnover markers in lumbar bones (alkaline phosphatase, tartarate resistant acid phosphatase, hydroxyproline) and urine (calcium). The bone loss was accompanied by reduced serum estradiol levels and bone TGF-β3 content. Preventive and curative treatment with raloxifene ameliorated bony alterations and was more effective than CVD. Deprived estrogen levels (that in turn reduced lumbar TGF-β3 content) following PHT and SVP, thus, might represent one of the various mechanisms of AEDs-induced bone loss. Raloxifene preserved the bony changes without interfering with their antiepileptic efficacy, and hence raloxifene could be a potential therapeutic option in the management of PHT and SVP-induced bone disease if clinically approved.

Keywords: antiepileptic drugs, osteoporosis, raloxifene, TGF-β3

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Authors: Jie Gao

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The combination of chemotherapy with gene therapy is highly effective in cancer therapy. To achieve combined therapeutic effects in human gastric cancer over expressing EGFR, we developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab’ for co-delivery of doxorubicin (DOX) and ribonucleotide reductase M2 (RRM2) siRNA (DOX-RRM2-TLPD). The results showed that EGFR was over expressed in several gastric cancer cell lines and gastric cancer tissues. Gene Expression Omnibus (GEO) results showed that RRM2 expression was significantly higher in gastric cancer than in non-gastric cancer tissue, and RRM2 siRNA inhibited the proliferation of several gastric cancer cells, indicating that RRM2 is a candidate target for gastric cancer therapy. Confocal studies and flow cytometry showed that DOX-RRM2-TLPD delivered DOX and RRM2 siRNA to EGFR over expressing gastric cancer cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity and apoptosis) compared with single-drug loaded or non-targeted controls, including DOX-NC-TLPD (targeted LPD co-delivering DOX and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and DOX-RRM2-NTLPD (non-targeted LPD co-delivering DOX and RRM2 siRNA). The in vivo antitumor assay showed that the average weight of the gastric cancer in mice treated with DOX-RRM2-TLPD was significantly lighter than that of mice treated with other controls. DOX-RRM2-TLPD represents an effective approach for combined therapy of gastric cancer over expressing EGFR.

Keywords: gene therapy, chemotherapy, immunoliposomes, gastric cancer

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Authors: Kinnsley Travis, Camerron M. Crowder

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Mapk8ip3 (Mitogen-Activated Protein Kinase 8 Interacting Protein 3) is a gene that codes for the JIP3 protein, which is a part of the JIP scaffolding protein family. This protein is involved in axonal vesicle transport, elongation and regeneration. Variants in the Mapk8ip3 gene are associated with a rare-genetic condition that results in a neurodevelopmental disorder that can cause a range of phenotypes including global developmental delay and intellectual disability. Currently, there are 18 known individuals diagnosed to have sequenced confirmed Mapk8ip3 genetic disorders. This project focuses on examining the impact of a subset of missense patient variants on the Jip3 protein function by overexpressing the mRNA of these variants in a zebrafish knockout model for Jip3. Plasmids containing cDNA with individual missense variants were reverse transcribed, purified, and injected into single-cell zebrafish embryos (Wild Type, Jip3 -/+, and Jip3 -/-). At 6-days post mRNA microinjection, morphological, behavioral, and microscopic phenotypes were examined in zebrafish larvae. Morphologically, we compared the size and shape of the zebrafish during their development over a 5-day period. Total locomotive activity was assessed using the Microtracker assay and patterns of movement over time were examined using the DanioVision assay. Lastly, we used confocal microscopy to examine sensory axons for swelling and shortened length, which are phenotypes observed in the loss-of-function knockout Jip3 zebrafish model. Using these assays during embryonic development, we determined the impact of various missense variants on Jip3 protein function, compared to knockout and wild-type zebrafish embryo models. Variants in the gene Mapk8ip3 cause rare-neurodevelopmental disorders due to an essential role in axonal vesicle transport, elongation and regeneration. A subset of missense variants was examined by overexpressing the mRNA of these variants in a Jip3 knock-out zebrafish. Morphological, behavioral, and microscopic phenotypes were examined in zebrafish larvae. Using these assays, the spectrum of disorders can be phenotypically determined and the impact of variant location can be compared to knockout and wild-type zebrafish embryo models.

Keywords: rare disease, neurodevelopmental disorders, mrna overexpression, zebrafish research

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Authors: Indu Barwal, Shloka Thakur, Subhash C. Yadav

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The plant virus capsid protein based nanoparticles are extensively studied for their application in biomedical research for development of nanomedicines and drug delivery systems. We have developed a chimeric drug delivery system by controlled in vitro assembly of separately bioconjugated fluorescent dye (as reporting molecule), folic acid (as receptor binding biomolecule for targeted delivery) and doxorubicin (as anticancer drug) using modified EDC NHS chemistry on heterologously overexpressed (E. coli) capsid proteins of cowpea chlorotic mottle virus (CCMV). This chimeric vehicle was further encapsidated on gold nanoparticles (20nm) coated with 5≠ thiolated DNA probe to neutralize the positive charge of capsid proteins. This facilitates the in vitro assembly of modified capsid subunits on the gold nanoparticles to develop chimeric GNPs encapsidated targeted drug delivery system. The bioconjugation of functionalities, number of functionality on capsid subunits as well as virus like nanoparticles, structural stability and in vitro assembly were confirmed by SDS PAGE, relative absorbance, MALDI TOF, ESI-MS, Circular dichroism, intrinsic tryptophan fluorescence, zeta particle size analyzer and TEM imaging. This vehicle was stable at pH 4.0 to 8.0 suitable for many organelles targeting. This in vitro assembled chimeric plant virus like particles could be suitable for ideal drug delivery vehicles for subcutaneous cancer treatment and could be further modified for other type of cancer treatment by conjugating other functionalities (targeting, drug) on capsids.

Keywords: chimeric drug delivery vehicles, bioconjugated plant, virus, capsid

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Authors: Gurfateh Singh, Mu Khan, Razia Khanam, Govind Mohan

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Objective: The present study has been designed to investigate the beneficial role of Fenofibrate & Clofibrate in attenuated the cardioprotective effect of ischemic preconditioning (IPC) in hyperlipidemic rat hearts. Materials & Methods: Experimental hyperlipidemia was produced by feeding high fat diet to rats for a period of 28 days. Isolated langendorff’s perfused normal and hyperlipidemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. The myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase-MB release to assess the extent of cardiac injury. Moreover, the oxidative stress in heart was assessed by measuring thiobarbituric acid reactive substance, superoxide anion generation and reduced form of glutathione. Results: The ischemia-reperfusion (I/R) has been noted to induce oxidative stress by increasing TBARS, superoxide anion generation and decreasing reduced form of glutathione in normal and hyperlipidemic rat hearts. Moreover, I/R produced myocardial injury, which was assessed in terms of increase in myocardial infarct size, LDH and CK-MB release in coronary effluent and decrease in coronary flow rate in normal and hyperlipidemic rat hearts. In addition, the hyperlipidemic rat hearts showed enhanced I/R-induced myocardial injury with high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of improvement in coronary flow rate and reduction in myocardial infarct size, LDH, CK-MB and oxidative stress. On the other hand, IPC mediated myocardial protection against I/R-injury was abolished in hyperlipidemic rat hearts. However, Treatment with Fenofibrate (100 mg/kg/day, i.p.), Clofibrate (300mg/kg/day, i.p.) as a agonists of PPAR-α have not affected the cardioprotective effect of IPC in normal rat hearts, but its treatment markedly restored the cardioprotective potentials of IPC in hyperlipidemic rat hearts. Conclusion: It is noted that the high degree of oxidative stress produced in hyperlipidemic rat heart during reperfusion and consequent down regulation of PPAR-α may be responsible to abolish the cardioprotective potentials of IPC.

Keywords: Hyperlipidemia, ischemia-reperfusion injury, ischemic preconditioning, PPAR-α

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Authors: Dwitya Elvira, Eryati Darwin

Abstract:

Background: Graves’ disease (GD) is an autoimmune thyroid disease. Imbalance of Th1/Th2 cells and T-regulatory (Treg)/Th17 cells was thought to play pivotal role in the pathogenesis of GD. Treg FoxP3 produced TGF-β to maintain regulatory function, and Th17 cells produced IL-17 as cytokines that were thought in mediating several autoimmune diseases. The aim of this study is to assess the role of IL-17 and TGF-β in the pathogenesis of GD and to investigate its correlation with Thyroid Stimulating Hormone Receptor Antibody (TRAb) and Treg FoxP3 expression. Method: 30 GD patients and 27 age and sex-matched controls were enrolled in this study. Diagnosis of GD was based on clinical and biochemical of GD. Serum IL-17, TGF-β, TRAb, and FoxP3 were measured by enzyme-linked immunosorbent assay (ELISA). Data were analyzed by using SPSS 21.0 (SPSS Inc.). Spearman rank correlation test was used for assessment of correlation. The statistical significance was accepted as P<0.05. Result: There was no significant correlation between IL-17 and TGF-β serum with expression of FoxP3 level in GD, but there was significant correlation between TGF-β and TRAb serum level (P<0.05). Serum levels of IL-17 and TGF-β were found to be elevated in patient group compared to control, where mean values of IL-17 were 14.43±2.15 pg/mL and TGF-β were 10.44±3.19 pg/mL in patients group; and in control group, level of IL-17 were 7.1±1.45 pg/mL and TGF-β were 4.95±1.35 pg/mL. Conclusion: Serum Il-17 and TGF-β were elevated in GD patients that reflect the role of inflammatory and regulatory cytokines activation in pathogenesis of GD. There was significant correlation between TGF-β and TRAb, revealing that Treg cytokines may play a role in pathogenesis of GD.

Keywords: IL-17, TGF-B, FoxP3, TRAb, Graves’ disease

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Authors: Fatimah Abd Elghani, Raymonde Szargel, Vered Shani, Hazem Safory, Haya Hamza, Mor Savyon, Ruth Rott, Rina Bandopadhyay, Simone Engelender

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Background: PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson’s disease. Down regulation of PINK1 results in abnormal mitochondrial morphology and altered membrane potential. Although PINK1 has a predicted mitochondrial import sequence, it’s cellular, and submitochondrial localization remains unclear, in part because it is rapidly degraded. In this work, we investigated the mechanisms involved in PINK1 degradation and how this may affect PINK1 stability and function, with implications for mitochondrial function in PD. In addition, pharmacological inhibition of proteasome activity was shown to lead to PINK1 accumulation, indicating that PINK1 degradation depends on the ubiquitin-proteasome system (UPS). Methods: Using co-immunoprecipitation assays, we identified E3 ubiquitin ligase SIAH1 as a PINK1-interacting protein in HEK293 cells as well as on rat brain tissues. In addition, we determined the effect of SIAH 1, SIAH2 and Parkin on PINK1 steady-state levels by Western blot analysis, and checked their possibility to ubiquitinate and mediate PINK1 degradation through the proteasome carried out in vivo ubiquitination experiments. Results: We have obtained results showing that SIAH-1 interacts with and ubiquitinates PINK1. The ubiquitination promoted by SIAH-1 leads to the proteasomal degradation of PINK1. We confirmed these findings by knocking down SIAH-1 and observing important accumulation of PINK1 in cells. Besides, we found that SIAH-1 decreases PINK1 steady-state levels but not the E3 ligase Parkin. We also investigated the interaction of SIAH-1 with PINK1 disease mutants and its ability to promote their ubiquitination and degradation. Although, no clear difference in the ability of SIAH-1 to promote the degradation of PINK1 disease mutants was observed. It is possible that dysfunction of proteasomal activity in the disease may lead to the accumulation and aggregation of ubiquitinated PINK1 in patients with PINK1 mutations, with possible implications to the pathogenesis of PD. Conclusions: Here, we demonstrated that SIAH-1 ubiquitinates and promotes the degradation of PINK1. In addition, SIAH-1 represents now a target that may help the improvement of mitophagy in PD. Further investigations needed to understand how mitophagy is regulated by PINK1-SIAH-1 axis to provide targets for future therapeutics.

Keywords: PD, Parkinson's disease, PINK1, PTEN-induced kinase1, SIAH, seven in absentia homolog, SN, substantia nigra

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Authors: Geliashvili T. M., Tyulyandina A. S., Valiev A. K., Kononets P. V., Kharatishvili T. K., Salkov A. G., Pronin A. I., Gadzhieva E. H., Parnas A. V., Ilyakov V. S.

Abstract:

Aim/Introduction: Metastasis (Mts) to the sternum, while extremely rare in differentiated thyroid cancer (DTC) (1), requires a personalized, multidisciplinary treatment approach. In aggressively growing Mts to the sternum, which rapidly become unresectable, a comprehensive therapeutic and diagnostic approach is particularly important. Materials and methods: We present a clinical case of solitary Mts to the sternum as first manifestation of a papillary thyroid microcarcinoma in a 55-year-old man. Results: 18F-FDG PET/CT after thyroidectomy confirmed the solitary Mts to the sternum with extremely high FDG uptake (SUVmax=71,1), which predicted its radioiodine-refractory (RIR). Due to close attachment to the mediastinum and rapid growth, Mts was considered unresectable. During the next three months, the patient received targeted therapy with the tyrosine kinase inhibitor (TKI) Lenvatinib 24 mg per day. 1st course of radioiodine therapy (RIT) 6 GBq was also performed, the results of which confirmed the RIR of the tumor process. As a result of systemic therapy (targeted therapy combined with RIT and suppressive hormone therapy with L-thyroxine), there was a significant biochemical response (decrease of serum thyroglobulin level from 50,000 ng/ml to 550 ng/ml) and a partial response with decrease of tumor size (from 80x69x123 mm to 65x50x112 mm) and decrease of FDG accumulation (SUVmax from 71.1 to 63). All of this made possible to perform surgical treatment of Mts - sternal extirpation with its replacement by an individual titanium implant. At the control examination, the stimulated thyroglobulin level was only 134 ng/ml, and PET/CT revealed postoperative areas of 18F-FDG metabolism in the removed sternal Mts. Also, 18F-FDG PET/CT in the early (metabolic) stage revealed two new bone Mts (in the area of L3 SUVmax=17,32 and right iliac bone SUVmax=13,73), which, as well as the removed sternal Mts, appeared to be RIRs at the 2nd course of RIT 6 GBq. Subsequently, on 02.2022, external beam radiation therapy (EBRT) was performed on the newly identified oligometastatic bone foci. At present, the patient is under dynamic monitoring and in the process of suppressive hormone therapy with L-thyroxine. Conclusion: Thus, only due to the early prescription of targeted TKI therapy was it possible to perform surgical resection of Mts to the sternum, thereby improve the patient's quality of life and preserve the possibility of radical treatment in case of oligometastatic disease progression.

Keywords: differentiated thyroid cancer, metastasis to the sternum, radioiodine therapy, radioiodine-refractory cancer, targeted therapy, lenvatinib

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Authors: Ramasamy Tamizhselvi, Leema George, Madhav Bhatia

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We have earlier shown that mouse pancreatic acinar cells produce hydrogen sulfide (H2S) and play a role in the pathogenesis of acute pancreatitis. This study is to determine the effect of H2S on TLR4 mediated innate immune signaling in acute pancreatitis via substance P (SP). Male Swiss mice were treated with hourly intraperitoneal injection of caerulein (50μg/kg) for 10 hour. DL-propargylglycine (PAG) (100 mg/kg i.p.), an inhibitor of H2S formation was administered 1h after the induction of acute pancreatitis. Pancreatic acinar cells from male Swiss mice were incubated with or without caerulein (10–7 M for 60 min) and CP-96345 (NK1R inhibitor). To better understand the effect of H2S in inflammation, acinar cells were stimulated with caerulein after addition of H2S donor, NaHS. In addition, caerulein treated pancreatic acinar cells were pretreated with PAG (30 µM), for 1h. H2S inhibitor, PAG, eliminated TLR4, IRAK4, TRAF6 and NF-kB levels in an in vitro and in vivo model of caerulein-induced acute pancreatitis. PPTA gene deletion reduced TLR4, MyD88, IRAK4, TRAF6, adhesion molecules and NF-kB in caerulein treated pancreatic acinar cells whereas administration of NaHS resulted in further rise in TLR4 and NF-kB levels in caerulein treated pancreatic acinar cells. In addition, acini isolated from mice and treated with PPTA gene receptor NK1R antagonist CP96345 did not exhibit further increase in TLR4, IRAK4, TRAF6, adhesion molecules and NF-kB levels after NaHS pretreatment. The present findings show for the first time that in acute pancreatitis, H2S up-regulates TLR4 pathway and NF-kB via substance P.

Keywords: preprotachykinin-A gene, H2S, TLR4, acute pancreatitis

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Authors: Najeeb Ullah Khan

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Background: The receptor activator NF-κβ ligand (RANKL) and Osteoprotegerin (OPG) polymorphisms have been associated with the progression of breast cancer to bone metastasis. Here, we aimed to investigate the association of RANKL and OPG gene polymorphism with breast to bone metastasis in the Pashtun population, Pakistan. Methods: Genomic DNA was obtained from all the study subjects (106 breast cancer, 58 breast to bone metastasis, and 51 healthy controls). RANKL (rs9533156) and OPG (rs2073618, rs3102735) polymorphisms were genotyped using Tetra-ARMS PCR. Results: Our results indicated that the frequencies of OPG (rs3102735) risk allele and genotypes carrying risk allele in breast cancer vs healthy control (C- p=0.005; CC- p=0.0208; TC- p=0.0181), bone metastasis vs healthy control (C- p=0.0211; CC- p=0.0153; TC- p=0.0775), and breast cancer vs breast to bone metastasis (C- p=0.0001; CC- p=0.0001; TC- p=0.001) were found significantly associated with disease risk. However, there was no significant association observed for OPG (rs2073618) risk allele and risk allele containing genotypes in all study groups. Similarly, RANKL (rs9533156) risk alleles and corresponding genotypes in breast cancer vs healthy control (C- p=0.0001; CC- p=0.0001; TC- p=0.0084), bone metastasis vs healthy control (C- p=0.0001; CC- p=0.0001; TC- p=0.5593), and breast cancer vs breast to bone metastasis (C- p=0.0185; CC- p=0.6077; TC- p=0.1436) showed significant association except for the risk allele carrying genotypes in breast cancer to bone metastasis (TC, p=0.1436; CC, p=0.6077). Conclusion: OPG (rs3102735) and RANKL (rs9533156) showed significant association with breast to bone metastasis, while OPG (rs2073618) didn’t show a significant association with breast to bone metastasis in Pashtun population of Pakistan. However, more investigation will be required to disseminate the results while gene sequencing or whole-exome sequencing.

Keywords: breast cancer, bone metastasis, OPG, RANKL, polymorphism

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Authors: Filip Franciszek Karuga, Szymon Turkiewicz, Marta Ditmer, Marcin Sochal, Piotr Białasiewicz, Agata Gabryelska

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Circadian rhythm, an internal coordinator of physiological processes is composed of a set of semi-autonomous clocks. Clocks are regulated through the expression of circadian clock genes which form feedback loops, creating an oscillator. The primary loop consists of activators: CLOCK, BMAL1 and repressors: CRY, PER. CLOCK can be substituted by the Neuronal PAS Domain Protein 2 (NPAS2). Orphan nuclear receptor (REV-ERB-α) is a component of the secondary major loop, modulating the expression of BMAL1. Circadian clocks might be disrupted by the obstructive sleep apnea (OSA), which has also been associated with type II diabetes mellitus (DM2). Interestingly, studies suggest that dysregulation of NPAS2 and REV-ERB-α might contribute to the pathophysiology of DM2 as well. The goal of our study was to examine the role of NPAS2 and REV-ERB-α in DM2 in OSA patients. After examination of the clinical data, all participants underwent polysomnography (PSG) to assess their apnea-hypopnea index (AHI). Based on the acquired data participants were assigned to one of 3 groups: OSA (AHI>30, no DM2; n=17 for NPAS2 and 34 for REV-ERB-α), DM2 (AHI>30 + DM2; n=7 for NPAS2 and 15 for REV-ERB-α) and control group (AHI<5, no DM2; n=16 for NPAS2 and 31 for REV-ERB-α). ELISA immunoassay was performed to assess the serum protein level of REV-ERB-α and NPAS2. The only statistically significant difference between groups was observed in NPAS2 protein level (p=0.037). Post-hoc analysis showed significant differences between the OSA and the control group (p=0.017). AHI and NPAS2 level was significantly correlated (r=-0.478, p=0.002) in all groups. A significant correlation was observed between the REV-ERB-α level and sleep efficiency (r=0.617, p=0.005) as well as sleep maintenance efficiency (r=0.645, p=0.003) in the OSA group. We conclude, that NPAS2 is associated with OSA severity and might contribute to metabolic sequelae of this disease. REV-ERB-α on the other hand can influence sleep continuity and efficiency.

Keywords: OSA, diabetes mellitus, endocrinology, chronobiology

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